rs3027875

Positions:

• chrX-153950388-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005334.3(HCFC1):​c.5859C>T​(p.Cys1953=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.414 in 111,874 control chromosomes in the GnomAD database, including 9,743 homozygotes. There are 13,393 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (9743 hom., 13393 hem., cov: 24)
  • Exomes 𝑓: 0.58 (136906 hom. 204100 hem.)
  • Failed GnomAD Quality Control
• Consequence: HCFC1 NM_005334.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.400

Genes affected

HCFC1 (HGNC:4839): (host cell factor C1) This gene is a member of the host cell factor family and encodes a protein with five Kelch repeats, a fibronectin-like motif, and six HCF repeats, each of which contains a highly specific cleavage signal. This nuclear coactivator is proteolytically cleaved at one of the six possible sites, resulting in the creation of an N-terminal chain and the corresponding C-terminal chain. The final form of this protein consists of noncovalently bound N- and C-terminal chains. The protein is involved in control of the cell cycle and transcriptional regulation during herpes simplex virus infection. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant X-153950388-G-A is Benign according to our data. Variant chrX-153950388-G-A is described in ClinVar as [Benign]. Clinvar id is 95281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153950388-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.4 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.639 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCFC1	NM_005334.3	c.5859C>T	p.Cys1953=	synonymous_variant	24/26	ENST00000310441.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCFC1	ENST00000310441.12	c.5859C>T	p.Cys1953=	synonymous_variant	24/26	1	NM_005334.3	P2
HCFC1	ENST00000369984.4	c.5994C>T	p.Cys1998=	synonymous_variant	24/26	5		A2
HCFC1	ENST00000444191.5	c.1587C>T	p.Cys529=	synonymous_variant	8/10	5

Frequencies

GnomAD3 genomes AF: 0.415 AC: 46362 AN: 111821 Hom.: 9747 Cov.: 24 AF XY: 0.393 AC XY: 13389 AN XY: 34033

Gnomad AFR AF: 0.0854

Gnomad AMI AF: 0.696

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.581

Gnomad EAS AF: 0.00394

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.567

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.644

Gnomad OTH AF: 0.414

GnomAD3 exomes AF: 0.426 AC: 75791 AN: 178057 Hom.: 13807 AF XY: 0.434 AC XY: 28382 AN XY: 65325

Gnomad AFR exome AF: 0.0706

Gnomad AMR exome AF: 0.204

Gnomad ASJ exome AF: 0.557

Gnomad EAS exome AF: 0.000817

Gnomad SAS exome AF: 0.141

Gnomad FIN exome AF: 0.600

Gnomad NFE exome AF: 0.648

Gnomad OTH exome AF: 0.490

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.576 AC: 631434 AN: 1096360 Hom.: 136906 Cov.: 40 AF XY: 0.563 AC XY: 204100 AN XY: 362246

Gnomad4 AFR exome AF: 0.0743

Gnomad4 AMR exome AF: 0.217

Gnomad4 ASJ exome AF: 0.549

Gnomad4 EAS exome AF: 0.000696

Gnomad4 SAS exome AF: 0.148

Gnomad4 FIN exome AF: 0.604

Gnomad4 NFE exome AF: 0.659

Gnomad4 OTH exome AF: 0.506

GnomAD4 genome AF: 0.414 AC: 46346 AN: 111874 Hom.: 9743 Cov.: 24 AF XY: 0.393 AC XY: 13393 AN XY: 34096

Gnomad4 AFR AF: 0.0852

Gnomad4 AMR AF: 0.297

Gnomad4 ASJ AF: 0.581

Gnomad4 EAS AF: 0.00395

Gnomad4 SAS AF: 0.127

Gnomad4 FIN AF: 0.567

Gnomad4 NFE AF: 0.644

Gnomad4 OTH AF: 0.407

Alfa AF: 0.535 Hom.: 6466

Bravo AF: 0.380

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 19, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Methylmalonic acidemia with homocystinuria, type cblX Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.26
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3027875; hg19: chrX-153215839; COSMIC: COSV60070177;